Process for the preparation of 1-indan-carboxylic acids and intermediate therefor

ABSTRACT

LEVOROTATORY 5-CYCLOHEXYL-1-INDANCARBOXYLIC ACID IS A USEFUL ANTI-INFLAMMATORY AGENT IN THE TREATMENT OF INFLAMMATORY DISEASES IN ANIMALS, INCLUDING MAN. AS SUCH, A NEW AND MORE EFFICIENT PROCESS HAS BEEN DISCOVERED FOR THE PREPARATION OF LARGE QUANTITIES OF THE COMPOUND.

United States Patent Oflice 6 Claims ABSTRACT OF THE DISCLOSURE Levorotatory S-cyclohexyl-l-indancarboxylic acid is a useful anti-inflammatory agent in the treatment of inflammatory diseases in animals, including man. As such, a new and more efiicient process has been discovered for the preparation of large quantities of the compound.

BACKGROUND OF THE INVENTION (1) Field of the invention The process of the present invention is a new and more efficient procedure for the preparation of large quantities of (i)-5-cyclohexyl-l-indancarboxylic acid.

(2) Description of the prior art The process of the present invention'is new and novel and produces yields several fold those obtained by the process described in US. patent application Ser. No. 858,870, filed Sept. 17, 1969, now US. Pat. No. 3,565,943.

The art most closely related to that of the process of the instant invention can be found in the following references:

(a) R. T. Hart and R. F. Tebbe, I. Am. Chem. Soc., 72, 3286 (1950).

(b) E. 1. Corey and D. Seebach, Angew. Chem., Int. Ed. Engl, 4, 1075 (1965).

(c) D. Seebach, Synthesis, 1, 17 (1969).

(d) D. Seebach, N.R. Jones, and E. J. Corey, J. Org. Chem., 33, 300 (1968).

SUMMARY OF THE INVENTION This invention is a new and novel process for the preparation of the compound having the formula which process comprises the consecutive steps of (A) Treating cyclohexylbenzene with ,B-chloropropionyl chloride in the presence of aluminum chloride followed by concentrated sulfuric acid to produce the com- 3,717,661 Patented Feb. 20., 1973 (B) Treating compound II with a solution of 1,3-dithiane activated with butyllithium to produce the compound having the formula III (C) Dehydrating compound III by treatment with ptoluenesulfonic acid to produce the compound having the formula and (D) Hydrolyzing Compound IV with aqueous acid to produce the compound having the Formula I.

DISCLOSURE OF THE INVENTION This invention relates to a new and novel and more efficient process for the preparation of nonsteroidal antiinflammatory agents having the name (i)-5-cyclohexyll-indancarboxylic acid, and more particularly the compound (-)-5-cyclohexyl-l-indancarboxylic acid which is the more potent isomer (U.S. patent application Ser. No. 858,870, filed Sept. 17, 1969).

The compounds produced by the process are characterized by the formula COzH The carbon to which the carboxyl group is attached is an asymmetric carbon atom such that the compounds exist in two isomeric forms; dextroand levorotatory isomers. Of these two isomers, the levorotatory isomer is the most potent isomer as an anti-inflammatory agent. However, the dextrorotatory isomer is also of importance inasmuch as it can be racemized to produce the desired levorotatory isomer.

It was an object of the instant invention to provide a new, novel and more eflicient process for the preparation of these compounds, said compounds being useful in the treatment of a variety of inflammatory diseases such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gout and other similar afllictions.

The process of the instant invention can be illustrated by the following diagram.

Steps A-C A1013, CS2

Step D S t t Li -on Tetrahydrofuran Compound II Step E S S p-toluenesulfonic acid H benzene, A i Compound 131 Step F C 02H H01, H20, CHaCOzH Compound IV I Step G (303E resolution Compound I la and The objectives of the present invention have been achieved by the provision of the process which comprises the consecutive steps of (A) Treating cyclohexylbenzene with a p-halopropionyl halide (chloro, brorno or iodo), but preferably chloro, in a ratio of at least 1 mole of the halopropionyl halide per mole of cyclohexylbcnzene, but preferably in a ratio of about 1.05 to 1, in the presence of an acylation catalyst selected from the group comprising AlCl SnCl ,v FeCl TiCl and Zncl but preferably AlCl in a ratio of at least 1 mole of acylation catalyst per mole of cyclohexylbenzene, but preferably in a ratio of about 1.2 to 1, in the presence of an organic solvent essentially inert to the reaction conditions selected from the group comprising carbon disulfide, methylene chloride, ethylene chloride, nitrobenzene and the like, but preferably carbon disulfide, for a period of 1 to 10 hours, but preferably about 2 to 5 hours, at room temperature;

(B) Adding a concentrated strong acid selected from the group comprising sulfuric acid, phosphoric acid, polyphosphoric acid, hydrofluoric acid and trifiuoroacetic acid, but preferably concentrated sulfuric acid, in a ratio of at least 3 moles of strong concentrated acid per mole of cyclohexylbenzene starting material, but preferably ina ratio of about 7 to 1;

(C) Heating, preferably in the range of about 75 C. to about C., to produce the compound having the formula (D) Treating Compound II with a compound having the formula in which Z is a radical of the formula S (0112) t l I W i i" S S, S\/S or S\/S in which X is a metal cation selected from the group comprising Li, Mg, Zn, Cd and Cu, but preferably Li, I: is an integer of 0 to 3, but is preferably 1, R and R are (lower)alkyl, y is an integer equal to the valence of X, in a ratio of at least 1 mole of the sulfur compound per mole of Compound II, but preferably in a ratio of about 1.2 moles of sulfur compound per mole of Compound II, at a temperature in the range of 20 C. to +25 C., but preferably at about 0 C., for a period of time of 5 to 30 hours, but preferably about 15 to 25 hours, to produce the compound having the formula in which Z is as defined above;

(E) dehydrating Compound III by treatment with a dehydrating agent selected from the group comprising: mineral acids such as sulfuric, phosphoric, phosphorous and hydrochloric; POCl SOCl arylsulfonic acids having the formula in which A, B or C are alike or different and are hydrogen, halogen, (lower)alkyl, (lower)alkoxy, nitro or cyano; activated carboxylic acids such as F CCO H,

and

wherein A, B, C are alike or different but are hydrogen,

nitro, fluoro or cyano; and alkylsulfonic acids having the formula in which R is (lower)alkyl, and the like, but preferably p-toluene-sulfonic acid, in an anhydrous organic solvent selected from the group comprising benzene, toluene, xylene, and the like, but preferably benzene, with the aid of heat, preferably at about reflux temperature, azeotropically removing the water so generated to produce the compound having the formula and (F) Hydrolyzing Compound IV with a mixture of concentrated hydrochloric acid and glacial acetic acid by heating at reflux temperatures for 1 to 5 hours, but preferably 2 to 3 hours, to produce the compound having the formula A preferred embodiment of the present invention is the process which comprises the consecutive steps of (A) Treating cyclohexylbenzene with a fl-halopropionyl halide of the formula in which X is bromo, iodo or chloro, in a ratio of at least 1 mole of the halopropionyl halide per mole of cyclohexylbenzene, in the presence of an acylation catalyst selected from the group comprising AlCl SnCl FeCl TiCl and ZnCl in a ratio of at least 1 mole of acylation catalyst per mole of cyclohexylbenzene, in the presence of an organic solvent essentially inert to the reaction conditions for a period of about 1 to hours, at room temperature;

(B) Adding a concentrated strong acid selected from the group comprising sulfuric acid, phosphoric acid, polyphosphoric acid, hydrofluoric acid and trifluoroacetic acid, in a ratio of at least 3 moles of strong concentrated acid per mole of cyclohexylbenzene starting material;

(C) Heating to produce the compound having the formula (D) Treating Compound II with a compound having the formula in which Z is a radical of the formula Z OH III

in which Z is as defined above;

(E) Dehydrating Compound III by treatment with a dehydrating agent selected from the group comprising: mineral acids such as sulfuric, phosphoric, phosphorous and hydrochloric; POCl SOCl arylsulfonic acids having the formula in which A, B or C are alike or different and are hydrogen, halogen, (lower)alkyl, (lower)alkoxy, nitro or cyano; activated carboxylic acids such as F C-CO H, F CH--CO H and wherein A, B, C are alike or different but are hydrogen, nitro, fluoro or cyano; and alkylsulfonic acids having the formula in which R is (lower)alkyl; n in an anhydrous organic solvent selected from the group comprising benzene, toluene and xylene, with the aid of heat, to produce the compound having the formula and (F Hydrolyzing Compound IV with a mixture of concentrated hydrochloric acid and glacial acetic acid by heating at reflux temperatures for l to hours, to produce the compound having the formula A more preferred embodiment is the process which comprises the consecutive steps of:

(A) Treating cyclohexylbenzene with a fi-halopropionyl halide of the formula in which X is chloro, bromo or iodo in a ratio of at least 1 mole of the halopropionyl halide per mole of cyclohexylbenzene, in the presence of an acylation catalyst selected from the group comprising A1013, SnCl FeCl TiCl and ZnCl in a ratio of at least 1 mole of acylation catalyst per mode of cyclohexylbenzene, in the presence of an organic solvent selected from the group comprising carbon disulfide, methylene chloride, ethylene chloride and nitrobenzene, for a period of l to hours, at room temperature; removing the solvent;

(B) Adding a concentrated strong acid selected from the group comprising sulfuric acid, phosphoric acid, polyphosphoric acid, hydrofluoric acid and trifiuoroacetic acid, in a ratio of at least 3 moles of strong concentrated acid per mole of cyclohexylbenzene starting material:

(C) Heating to produce the compound having the formula (D) Treating Compound II with a compound having the formula in which Z is a radical of the formula {V51 si /EL) or If I;

time of 5 to 30 hours, to produce the compound having the formula Z OH in which Z is as defined above;

(E) Dehydrating Compound III by treatment with a dehydrating agent selected from the group comprising: POCl SOCl arylsulfonic acids having the formula SOaH in which A, B or C are alike or different and are hydrogen, halogen, (lower)alkyl, (lower)alkoxy, nitro or cyano; and alkylsulfonic acids having the formula in which R is (lower)alkyl; in an anhydrous organic solvent selected from the group comprising benzene, toluene and xylene, with the aid of heat, to produce the compound having the formula (F) Hydrolyzing Compound IV with a mixture of concentrated hydrochloric acid and glacial acetic acid by heating at reflux temperatures for 1 to 5 hours, to produce the compound having Formula 1.

Another more preferred embodiment is the process of which comprises the consecutive steps of:

(A) Treating cyclohexylbenzene with fi-chloropropionyl chloride in a ratio of at least 1 mole of the halopropionyl halide per mole of cyclohexylbenzene, in the presence of an acylation catalyst selected from the group comprising AlCl SnCI FeCl TiCL; and ZnCl in a ratio of at least 1 mole of acylation catalyst per mole of cyclohexylbenzene in the presence of an organic solvent selected from the group comprising carbon disulfide, methylene chloride, ethylene chloride and nitrobenzene, for a period of 1 to 10 hours, at room temperature; removing the solvent in vacuo;

(B) Adding concentrated sulfuric acid in a ratio of at least 3 moles of acid per mole of cyclohexylbenzene starting material;

(C) Heating in the range of about 75 C. to about C., to produce the compound having the formula and II (D) Treating Compound H with a compound having in a ratio of 1.2 moles of sulfur compound per mole of Compound II, at a temperature of about 0 C,, for a period of time of about 15 to 25 hours, to produce the compound having the formula (E) Dehydrating Compound III by treatment with a dehydrating agent selected from the group comprising arylsulfonic acids having the formula in which A and B are alike or different and are hydrogen or (lower)alkyl in an anhydrous organic solvent selected from the group comprising benzene, toluene and xylene, with the aid of heat at about reflux temperature, azeotropically removing the water so generated to produce the compound having the formula and (F) Hydrolyzing Compound IV with a mixture of concentrated hydrochloric acid and glacial acetic by heating at reflux temperatures for about 1 to hours, to produce the compound having Formula I.

A most preferred embodiment is the process of which comprises the consecutive steps of:

(A) Treating cyclohexylbenzene with B-chloropropionyl chloride, in a ratio of about 1.0 to 1.1 moles of acylchloride per mole of cyclohexylbenzene in the presence of AlC1 in a ratio of about 1.1 to 1.3 moles of AlCl per mole of cyclohexylbenzene, in the presence of an organic solvent selected from the group comprising carbon disulfide, methylene chloride, ethylene chloride and nitrobenzene, for a period of about 2 to 5 hours at room temperature; removing the solvent in vacuo;

(B) Adding concentrated sulfuric acid in a ratio of about 5 to moles of sulfuric acid per mole of cyclohexylbenzene starting material;

(C) Heating in the range of about 75 C. to about 125 C., to produce the compound having the formula (D) Treating Compound II with a compound having 10 in a ratio of about 1.1 to 1.3 moles of the sulfur compound per mole of Compound II, at a temperature of about 0 C., for a period of time of about 15 to 25 hours, to produce the compound having the formula s s \on (E) Dehydrating Compound III by treatment with a catalytic quantity of p-toluenesulfonic acid, in an anhydrous organic solvent selected from the group comprising benzene, toluene and xylene, at about reflux temperature, azeotropically removing the water so generated to produce the compound having the formula and (F) Hydrolyzing Compound IV with a mixture of concentrated hydrochloric acid and glacial acetic acid by heating at reflux temperatures for about 2 to 3 hours, to produce the compound having Formula I.

Another most preferred embodiment is the process of which comprises the consecutive steps of:

(A) Treating cyclohexylbenzene with fl-chloropropionyl chloride, in a ratio of about 1.0 to 1.1 moles of acylchloride per mole of cyclohexylbenzene in the presence of A101 in a ratio of about 1.1 to 1.3 moles of AlCl per mole of cyclohexylbenzene, in the presence of carbon disulfide, for a period of about 2 to 5 hours at room temperature, removing the solvent in vacuo;

(B) Adding concentrated sulfuric acid in a ratio of about 5 to 10 moles of sulfuric acid per mole of cyclohexylbenzene starting material;

(C) Heating in the range of about C. to about C., to produce the compound having the formula (D) Treating Compound II with a compound having in a ratio of about 1.1 to 1.3 moles of the sulfur compound per mole of Compound II, at a temperature of about C., for a period of time of about 15 to 25 hours, to produce the compound having the formula III (E) Dehydrating Compound III by treatment with a catalytic quantity of p-toluenesulfonic acid, in an anhydrous organic solvent selected from the group comprising benzene, toluene and xylene, at about reflux temperature, azeotropically removing the water so generated to produce the compound having the formula and (F) Hydrolyzing Compound IV with a mixture of concentrated hydrochloric acid and glacial acetic acid by heating at reflux temperatures for about 2 to 3 hours, to produce the compound having Formula I.

The process of the instant invention produces yields superior to those obtained by the process taught in U.S. patent application Ser. No. 858,870, filed Sept. 17, 1969.

For example, the process described in Ser. No. 858,870 involves seven separate and tedious steps starting with cyclohexylbenzene and produces overall yields of Compound I of about The process of the instant invention however, involves but four steps and produces overall yields of about 37% of Compound I based on cyclohexylbenzene.

For the purpose of this disclosure, the term lower alky shall mean a straight or branched chain aliphatic hydrcoarbon of 1 to 6 carbon atoms. The term (lower) in (lower)alkoxy shall have the same connotation.

Another preferred embodiment is the ()a-(1-naphthyl)ethylamine salt of (-)-5-cyclohexyl-l-indancarboxylic acid.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Example 1 Preparation of S-cyclohexyl-l-indanone.A solution of fl-chloropropionyl chloride (13.33 g., 0.105 mole) and cyclohexylbenzene (16.03 g., 0.1 mole) in carbon disulfide (25 ml.) was added dropwise with stirring over a period of minutes to a cooled (ice-water) suspension of aluminum chloride (16.0 g., 0.12 mole) in carbon disulfide (60 ml). The mixture was then stirred at room temperature for 3 hours. The mixture was concentrated in a rotary evaporator. Sulfuric acid (250 ml. of specific gravity 1.84) was added slowly with stirring and cooling (ice water) to the residual oil. After the addition was complete the mixture was stirred at room temperature for 15 minutes. The mixture was then heated by means of an oil bath, the temperature of which was slowly raised to C. and maintained at this temperature for 2 hours. The mixture was then allowed to stand at room temperature for 15 hours. The mixture was poured onto ice (1 kg). The resulting mixture was extracted with diethyl ether (3X 500 ml.). The combined ether solution was washed with water '(250 ml.) followed by saturated aqueous sodium bicarbonate (200 ml), and saturated aqueous sodium chloride (2X 200 ml.). The washed solution was dried over anhydrous sodium sulfate and concentrated in a rotary evaporator to give a yellow-brown solid (19.7 g.), M.P. 64-73 C. The product was recrystallized with charcoal treatment from n-pentane to give S-cyclohexyll-indanone (14.7 g.) as yellow crystals, M.P. 75-765" C. Recrystallization with charcoal treatment from n-pentane gave oif-white crystals, M.P. 75.577 C.

Analysis.Calcd for C H O (percent): C, 84.07; H, 8.47. Found (percent): C, 83.99; H, 8.43.

Referencet R. T. Hart and R. F. Tebee, I. Am. Chem. Soc., 72, 3286 (1950).

Example 2 Preparation of 5-cyclohexyl-1-[2-(l,3-dithianyl)]-1-hydroxyindan.All the reactants in the following sequence were protected by an atmosphere of nitrogen. A solution of n-butyllithium in hexane (30 ml. of 1.6 M, 0.048 mole of n-butyllithium) was added over about 15 minutes to a cooled (*25 C.) solution in 1,3-dithiane (6.0 g., 0.05 mole) in tetrahydrofuran (66- ml.). The resulting solution was allowed to warm to -15 C. and was then stirred at this temperature for 2 hours. The temperature of the solution was adjusted to 2 C. over about 30 minutes, when a solution of S-cyclohexyl-l-indanone (8.6 g., 0.04 mole) in tetrahydrofuran (215 ml.) was added over a period of 1 hour while the temperature of the reaction solution was maintained at 0 C. The solution was then allowed to stand at 0 C. for 20 hours. The tetrahydrofuran and hexane solvents were removed under reduced pressure. The residue was partitioned between diethyl ether and 5% aqueous hydrochloride acid. The ether layer was washed successively with 5% aqueous hydrochloric acid, water, and saturated aqueous sodium chloride, and then concentrated to give 5-cyclohexyl-1-[2-( l,3-dithianyl)]-l-hydroxyindan (15.6 g.) as an orange oil.

References: (1) E. 1. Corey and D. Seebach, Angew. Chem., Int. Ed. Engl, 4, 1075 (1965).

(2) D. Seebach, Synthesis, 1, 17 (1969).

(3) D. Seebach, N. R. Jones, and E. J. Corey, J. Org. Chem. 33, 300 (1968).

Example 3 5-cyc1ohexyl-1-[2-( 1 ,3-dithianylidene) indan. A solution of crude 5-cyclohexyl- 1 [2-(1,3-dithianyl)-1-hydroxyindan (15.6 g.) and p-toluenesulfonic acid monohydrate (1.6 g.) in benzene (200 ml.) was heated under reflux for 30 minutes with continuous removal of the water formed. The cooled solution was washed successively with water, saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, and was then dried over sodium sulfate. Removal of the solvent gave 5-cyclohexyl-1-[2-(1,3-dithianylidene)]indan (13.7 g.) as a brown oil. This crude material was used directly in the next step of the synthesis.

Crude material from other similar experiments was purified by chromatography on silicic acid with n-pentane. The purified material was recrystallized three times from n-hexane to give S-cyclohexyl-1-[2-(1,3-dithianylidene)] indan as ofi-white crystals, M.P. 79-80" C.

Analysis.-Calcd for C I-1 8 (percent): C, 72.10; H, 7.64; S, 20.26. Found (percent): 72.19; H, 7.75; S, 20.05.

Example 4 Preparation of (i )-5-cyclohexyl 1 indancarboxylic acid.A mixture of crude 5-cyclohexyl-1-[2-(1,3-dithianylidene)]indan (13.7 g.), glacial acetic acid (210 m1.) and concentrated hydrochloric acid (70 ml.)was heated under reflux for 2 hours. The cooled mixture was concentrated in a rotary evaporator. The residue was dissolved in toluene and the toluene solution was reduced to dryness. The toluene treatment was repeated in order to remove residual actic acid. A methylene chloride solution of the residue was washed with water until the washings were neutral to pH paper. The solution was then exhaustively extracted with aqueous potassium carbonate. The combined carbonate solution was washed with methylene chloride and then stirred at room temperature with activated charcoal. The mixture was filtered, and the filtrate acidified with concentrated hydrochloric acid. The precipitated solid (5.9 g.), M.P. l44145 C., was recrystallized from Skellysolve B (essentially n-hexane) to give (i)-5-cyclohexyl-l-indancarboxylic acid (5.2 g.), M.P. 145-146" C.

The product so obtained was essentially identical to authentic (i)-5-cyclohexyl-l-indancarboxylic acid obtained by the method described in US. patent application Ser. No. 858,870, Example 1.

Reference: D. Seebach, Synthesis, 1, 17 (1969).

EXAMPLE 5 of ()-5-cyclohexyl-l-indancarboxylic acid.A solution of ()-m-(1-ntphthyl)ethylamine (1.76 g., 0.01025 mole) in acetonitrile (2 ml.) was added to a boiling solution of '-)-5-cyclohexyl-l-indancarboxylic acid (5.0 g., 0.0205 mole) in acetonitrile (250 ml.). The boiling solution was partially cooled and was then seeded with the (-)-u-(lnaphthyl)ethylamine salt of authentic ()-5-cyclohexyll-indancarboxylic acid. The mixture was allowed to cool slowly and then stand at 25 C. for 3 hours. The crystals were collected and washed with cold acetonitrile to give the ()-e-(1-naphthyl)ethylamine salt of the ()-acid (3.5 g.), M.P. 156160 C. This salt was dissolved in boiling acetonitrile (200 ml.) and the volume of the solution reduced to about 100 ml. by boiling. The solution was seeded with the ()-a-(l-naphthyl)ethylamine salt of authentic* (-)-5-cyclohexyl-l-indancarboxylic acid and allowed to cool slowly and then stand at 25 C. for 3 hours. The crystals were collected and washed with cold acetonitrile to give material (3.2 g.) with M.P. 161162 C. Recrystallization from acetonitrile gave the salt (3.0 g.) with M.P. 163-164" C. The latter material was partitioned between ethyl acetate (20 ml.) and 0.5 N hydrochloric acid (20 ml.). The ethyl acetate layer was washed successively with 1 N hydrochloric acid ml.), water (2x 10 ml.), and saturated aqueous sodium chloride (10 ml.). The ethyl acetate solution was dried (sodium sulfate) and reduced to dryness to give a solid (1.68 g.), M.P. 108-110 C. with prior softening. Recrystallization from petroleum ether (B.P. 39-50 C.) gave ()-5-cyclohexyl-l-indancarboxylic acid (1.51 g.) as colorless crystals; M.P. 108-l10 C.; 9.69 (c. 2, absolute ethanol) and [a] 44.76 (c. 2, absolute ethanol).

EXAMPLE 6 Racemization of enriched (+)-5-cyclohexyl 1 indancarboxylic acid to (i)-5-cyclohexyl-l-indancarboxylic acid The mother liquors obtained in Example 5 after the removal by filtration of the (-)-a-(1-naphthyl)ethylamine salt of ()-5-cyclohexyl-l-indancarboxylic acid were taken to dryness in vacuo. The semi-solid was layered *The ()-a-(I-naphthyDethylamlne salt of ()-5-cyclohexyl-l-lndancarboxylic acid was prepared from authentic ()-5-cyclohexyl-l-indanearboxylic acid obtained by the methods taught in Examples 1 and 4 of U.S. patent application Ser. No. 858,870. The salt seed crystals were prepared by the method taught above wherein ()-5-clcyohexyl-1-indancarboxyllc acid is treated with ()-a-(1-naphthyl)-ethylamlne in bolllng acetonitrile, followed by cooling and scratching with a glass rod to induce crystallization. The crystals were collected by filtration and dried.

with benzene and then treated with an excess of 10% hydrochloric acid. After the solids dissolved, the benzene layer was collected, washed with water and taken to dryness in vacuo. The semi-solids were dissolved in methylene chloride and dimethylformamide and treated with thionyl chloride. The mixture was refluxed 2 to 3 hours. The mixture was taken to dryness in vacuo, following which fresh methylene chloride was added, and then the solution was again taken to dryness in vacuo. The oil was dissolved in methylene chloride and the resultant solution was added to cold methanol (slowly) while keeping the temperature below 20 C. The mixture was refluxed for 30 minutes following which the mixture was taken to dryness in vacuo. The product was determined to be essentially pure methyl ester of the enriched S-cyclohexyl-l-indancarboxylic acid.

The methyl ester was dissolved in isopropanol following which sodium methoxide was added with temperature control to prevent the temperature from rising above 25 C. The mixture was kept at 25 C. for 15 minutes following which it was warmed to 4550 C. for 30 minutes.

Water was added to the mixture and the solution was refluxed for 3 hours. The solution turned black (pH--l1- 12). The pH was adjusted to 7.6 with 6 N hydrochloric acid and then treated with activated charcoal. The activated charcoal was removed by filtration and the essentially colorless solution was adjusted to pH 7.0. The solution became turbid. Seed crystals of (i)-5-cyclohexyl-lindancarboxylic acid were added and the pH further adjusted to 1.5 with stitrring over a 30 minute period. The product crystallized. Additional water was added and the mixture was cooled at 0-5 C. for 1 hour. The product was collected by filtration and was determined to be (i)- 5-cyclohexyl-l-indancarboxylic acid. The racemic product can then be resolved by the procedure of Example 5 into additional ()-5-cyclohexyl-l-indancarboxylic acid.

We claim:

1. A process for the preparation of the compound having the formula which process comprises the consecutive steps of (A) treating cyclohexylbenzene with a fi-halopropionyl halide of the formula in which X is bromo, iodo or chloro, in a ratio of at least 1 mole of the halopropionyl halide per mole of cyclohexylbenzene, in the presence of an acylation catalyst selected from the group comprising AlCl SnCl FeCl TiCl and ZnCl in a ratio of at least 1 mole of acylation catalyst per mole of cyclohexylbenzene, in the presence of an organic solvent essentially inert to the reaction conditions, for a period of about 1 to 10 hours, at about room temperature;

(B) adding a concentrated strong acid selected from the group comprising sulfuric acid, phosphoric acid, polyphosphoric acid, hydrofluoric acid and trifluoroacetic acid, in a ratio of at least 3 moles of strong concentrated acid per mole of cyclohexylbenzene starting material;

1 (C) heating to produce the compound having the formula (D) treating Compound H with a compound having the formula in which Z is a radical of the formula S g t t S S L or E l A X is a metal cation selected from the group comprising Li, Mg, Zn, Cd, and Cu, n is an integer of O to 3, R and R are (lower)alkyl, y is an integer equal to the valence of X, in a ratio of at least 1 mole of the sulfur compound per mole of Compound II, at a temperature in the range of -20 C. to +25 C., for a period of time of 5 to 30 hours, to produce the compound having the formula III in which Z is as defined above;

(E) dehydrating Compound III by treatment with a dehydrating agent selected from the group comprising: mineral acids selected from the group comprising sulfuric, phosphoric, phosphorous and hydrochloric acid, POCl SOCI arylsulfonic acids having the formula in which A, B or C are alike or different and are hydrogen, halogen, (lower)alkyl, (lower)alkoxy, nitro or cyano; activated carboxylic acids such as F C-CO H, F CHCO H and wherein A, B, C are alike or different but are hydrogen, nitro, fluoro or cyano; and alkylsulfonic acids having the formula in which R is (lower) alkyl; in an anhydrous organic solvent selected from the group comprising benzene, toluene and xylene, with the aid of heat, to produce the compound having the formula 16 and (F) hydrolyzing Compound IV with a mixture of concentrated hydrochloric acid and glacial acetic acid by heating at reflux temperatures for 1 to 5 hours, to produce the compound having Formula I.

2. The process of claim 1 which comprises (A) treating cyclohexylbenzene with a [i-halopropionyl halide of the formula in which X is chloro, bromo or iodo in a ratio of at least 1 mole of the halopropionyl halide per mole of cyclohexylbenzene, in the presence of an acylation catalyst selected from the group comprising AlCl SnCl FeCl TiCl and ZnCl in a ratio of at least 1 mole of acylation catalyst per mole of cyclohexylbenzene, in the presence of an organic solvent selected from the group comprising carbon disulfide, methylene chloride, ethylene chloride and nitrobenzene, for a period of 1 to 10 hours, at room temperature; removing the solvent;

(B) adding a concentrated strong acid selected from the group comprising sulfuric acid, phosphoric acid, polyphosphoric acid, hydrofluoric acid and trifiuoroacetic acid, in a ratio of at least 3 moles of strong concentrated acid per mole of cyclohexylbenzene starting material;

(C) heating to produce the compound having the formula (D) treating Compound II with a compound having the formula in which Z is a radical of the formula S S S YYY in which X is a metal cation selected from the group comprising Li, Mg, Zn, Cd and Cu, n is an integer of 1 to 2, R and R are (lower) alkyl, y is an integer equal to the valence of X, in a ratio of at least 1 mole of the sulfur compound per mole of Compound II, at a temperature in the range of 20 C. to +25 C., for a period of time of 5 to 30 hours, to produce the compound having the formula ZOH III

in which Z is as defined above;

(E) dehydrating Compound III by treatment with a dehydrating agent selected from the group comprising: POCl SOCI arylsulfonic acids having the formula 17 in which A, B or C are alike or diiferent and are hydrogen, halogen, (lwer)alkyl, (lower)alkoxy, nitro or cyano; and alkylsulfonic acids having the formula R--SO H in which R is (lower)al=kyl; in an anhydrous organic solvent selected from the group comprising benzene, toluene and xylene, with the aid of heat, to produce the compound having the formula (F) hydrolyzing Compound IV with a mixture of concentrated hydrochloric acid and glacial acetic acid by heating at reflux temperatures for l to hours, to produce the compound having Formula I.

3. The process ofclaim 1 which comprises (A) treating cyclohexylbenzene with B-chloropropionyl chloride in a ratio of at least 1 mole of the halopropionyl halide per mole of cyclohexylbenzene, in the presence of an acylation catalyst selected from the group comprising AlCl SnCl FeCl TiCl and ZnCl in a ratio of at least 1 mole of acylation catalyst per mole of cyclohexylbenzene, in the presence of an organic solvent selected from the group comprising carbon disulfide, methylene chloride, ethylene chloride and nitrobenzene, for a period of 1 to hours, at room temperature; removing the solvent;

(-B) adding concentrated sulfuric acid in a ratio of at least 3 moles of acid per mole of cyclohexylbenzene starting material;

(C) heating in the range of about 75 C. to about 125 C., to produce the compound having the formula ('D) treating Compound II with a compound having the formula in a ratio of 1.2 moles of sulfur compound per mole of Compound II, at a temperature of about 0 C., for a period of time of about to 25 hours, to produce the compound having the formula 18 (E) dehydrating Compound III by treatment with a dehydrating agent selected from the group comprising arylsulfonic acids having the formula the formula and ( F) hydrolyzing Compound IV with a mixture of concentrated hydrochloric acid and glacial acetic acid by heating at reflux temperatures for about 1 to 5 hours, to produce the compound having formula I.

I 4. The process of claim 1 which comprises (.A) treating cyclohexylbenzene with fi-chloropropionyl chloride, in a ratio of about 1.0 to 1.1 moles of acyl chloride per mole of cyclohexylbenzene in the presence of AlCl in a ratio of about 1.1 to 1.3 moles of A1013 per mole of cyclohexylbenzene, in the presence of an organic solvent selected from the group comprising carbon d'isulfide, methylene chloride, ethylene chloride and nitrobenzene, for a period about 2 to 5 hours at room temperature; removing the solvent in vacuo;

(B) adding concentrated sulfuric acid in a ratio of about 5 to 10 moles of sulfuric acid per mole of cyclohexylbenzene starting material;

(C) heating in the range of about 75 C. to about C., to produce the compound having the formula (D) treating Compound II with a compound having the formula S Li in a ratio of about 1.1 to 1.3 moles of the sulfur compound per mole of Compound II, at a temperature of about 0 C., for a period of time of about 15 to 19 25 hours, to produce the compound having the formula (E) dehydrating Compound III by treatment with a catalytic quantity of p-tolucnesulfonic acid, in an anhydrous organic solvent selected from the group comprising benzene, toluene and xylene, at about reflux temperature, azeotropically removing the water so generated to produce the compound having the forand (F) hydrolyzing Compound IV with a mixture of con centrated hydrochloric acid and glacial acetic acid by heating at reflux temperatures for about 2 to 3 hours, to produce the compound having Formula I.

5. The process of claim 1 which comprises (A) treating cyclohexylbenzene with p-chloropropionyl chloride, in a ratio of about 1.0 to 1.1 moles of acyl chloride per mole of cyclohexylbenzene in the presence of AlCl in a ratio of about 1.1 to 1.3 moles of AlCl per mole of cyclohexylbenzene, in the presence of carbon disulfide, for a period of about 2 to 5 hours at room temperature; removing the solvent in vacuo;

(B) adding concentrated sulfuric acid in a ratio of about 5 to moles of sulfuric acid per mole of cyclohexylbenzene starting material;

(C) heating in the range of about 75 C. to about 125 C., to produce the compound having the formula (D) treating Compound II with a compound having the formula in a ratio of about 1.1 to 1.3 moles of the sulfur compound per mole of Compound II, at a temperature of about 0 C., for a period of time of about 15 to 25 hours, to produce the compound having the formula \COH o 1;

(E) dehydrating Compound III by treatment with a catalytic quantity of p-toluenesulfonic acid, in an anhydrous organic solvent selected from the group comprising benzene, toluene and xylene, at about reflux temperature, azeotropically removing the water so generated to produce the compound having the for- (F) hydrolyzing Compound IV with a mixture of concentrated hydrochloric acid and glacial acetic acid by heating at reflux temperatures for about 2 to 3 hours, to produce the compound having the Formula I.

6. The compound having the formula References Cited UNITED STATES PATENTS 3,565,943 2/1971 Juby ct a1. 260--515 R JAMES A. PATTEN, Primary Examiner US. Cl. X.R.

260-327 T, 501.1, 515 R, 590, 592, 609 D 

